Abstract Our laboratory was the first to demonstrate unequivocally that several isoforms of small conductance Ca2+- activated K+ channels (SK or KCa2 channels) underlie Ca2+-activated K+ current (IK,Ca) in cardiomyocytes. Indeed, interests in cardiac SK channels are fueled by recent studies suggesting the possible roles of SK channels in human atrial fibrillation (AF) and up-regulation of SK channels in heart failure (HF). Therefore, SK channel may represent a novel therapeutic target for cardiac arrhythmias. Even though the activation and trafficking of SK channels are Ca2+-dependent, the Ca2+ source remains undefined. In addition, the Ca2+-dependence of SK channels is inextrictably linked to calmodulin (CaM), whose mutations have been shown to be associated with human arrhythmias. Since CaM is ubiquitous, it is paramount to disentangle the web of CaM-regulated ion channels from the roles of SK channels in calmodulinopathy. Moreover, SK channel expression is upregulated in HF but the exact mechanisms remain incompletely understood. Blockade of SK channels has been shown to be both anti-arrhythmic and proarrhythmic in various models. These aforementioned challenges are the premises of the present proposal. Thus, the essence of this proposal is to deploy innovative imaging, functional analyses, and molecular modeling to address successively the regulation of cardiac Ca2+-activated K+ channels in normal and failing cardiac myocytes.